Process of preparing allylic substituted acetic acids



Patented Oct. 17, T1950 UNITED STATES rATENT OFFICE PROCESSOF PREPARING- ALLYLIC SUBSTITUTED ACETIC ACIDS Richard T.7Arnold, St. Paul, Minn.

No Drawing.

Application December 31, 1947, Serial No. 795,121

7 claims. (01. 2so-515) -The present invention relates to the introduction' of allylic groups into the carbonyl group of esters of aromatic-substitut ed acids, and'more particularly it relates to the introduction of allylic groups into the alpha position of aromatic substituted acetic acid.

I These compounds are useful in various organic syntheses,-'and particularly in the production of certain analgesics, for example the production of 4,4'-diphenyl-6 dimethylamino-heptanone-3 from diphenyl allyl acetic acid. a p In the past 'diphenyl allyl 'acetic'acid has been obtained by the 'reaction of b'enzyl 1 diphenylacetate with an allyl halide in the presence ofsome strong base, which results in'the introduction of the allyl. group on Thereafter the ester group is removed by hy-' drolysis. This method has left m'uch tobe' desired-inasmuch as the hydrolysis step entails variousdifiiculties including the distinct possibility of lactone formation; According to the the alpha position ofthe: alpha-carbon atom..

present. methodthis hydrolysis step is obviated l and the}. processing proceeds. to good yields in a simple: ifianner. I I Y Y Broadly the invention involves the rearrangement of an allylic' ester'of aromatic-substituted 1 acetic acids such that the allyl-grou'p is introduced into the alpha position. Thisrea'ction is found to occur in-the presence of basic reagents.

: It: is, therefore, an object of the 'presentfirivention toprovide a process for the introduction of allylic groups into the alpha position of an aromatic-substituted acetic acid. It is a further object'of the present invention to provide 'anovelprocess for producingdip'henyl ally] .acetic acid and related; compounds;

The invention involvesthezconvers o of esters offlthe following type: q

(R1) 1-n 2 Bi 4 following formula:

phenyl, substituted phenyl, naphthyl, and the like ;'R1 example methyl, ethyl, propyl, and the like; R2, R3, andR may bealike r different and may be hydrogen or aliphatic ra'dicals,such as methyl, ethyl, propyl, and the like; and n is an integer not greater than 2;

j The present invention'may be carried out on any of the starting materials contemplated herein'lby means of a basic reagent which is able to is an aliphatic hydrocarbon radical, for

into allylic substituted acetic acids havingthe,

: v 50. in which is anaromatic radical, ,for example bring about the ionization of the original. ester to form an anion which then undergoes spontaneous internal rearrangement to form the anion of the desired acid. This is shown by the following equation:

c There is a wide variety of basic reagents which are capable of effecting the desired ionization of the original ester. In general hydrides, amides, and alkoxides of active metals such as sodium, potassium, and "the .like, fand also Grignard, reagents, will"bring abo 1it" this rearrangement, of; 'allylic esters. Suitable basic reagents "include the following; NaNHz,NaN( Cz'I-I5), KNHz, na'ocrn, NaOCzI-Is; KOC (CH3) 3', and RMgX where R is alkyl or aryl, and X is Cl, Br, or I. .1 I "f I A typical reaction may be illustrated by means of the following equation showing the produc-i tion of diphenyl'allyl' acetic acidvby threaction of sodium hydride on allyl diphenyl acetate;

. CHzr-dHCEz v j This method involves the direct" substitution of the alpha-hydrogen atom by the 'allyl group when the allyl ester is-treated witha strong base to form the sodium salt of alpha-allyl diphenyl acetic acid'directly byan intra-molecular rearrangement of the anion formed from-the ester by means of the strong base. In thisman'ner the difficulty of hydrolyzing the ester involved in previously used syntheses is completely elimi--, nated a 5 NSI Another advantage of the present synthesis lies in the ability to prepare isomeric allylic acids by the appropriate choice of starting materials. Thus it has been shown that the allylic group in the original allylic ester undergoes an inversion (alpha, gamma) during the internal rearrange.- ment. This has been demonstrated by the synthesis of alpha-crotyl-diphenyl acetic acid from i'socrotyl diphenyl acetate and by. the synthesis of alpha-isocrotyl diphenyl acetic acid from ncrotyl diphenyl acetate. These reactions. are illustrated as follows:

NaH

The reaction. may be. carried out preferably under anhydrous conditions by simply mixing the allyl. ester with. the basic reagent. in. a suitable.

inert solventjwhic'h includes ethers such as. diethyl ether, dioxane, a wide variety of hydrocarbonssuch as benzene, toluene, petroleum ether and. the like, alcohols when their. alkoxides. are employedas the basic reagent In some instances the. reaction is exothermic and} proceeds without the application of heat. may be desirable to warm the reaction mixture under reflux for a short periodpf time and then allow an extended period of time for the reaction to be carried out; Considerable variation is therefore possible in the specific reaction conditions which may be employed, depending upon the particular ester, the basic reagent, the solvent, and the like.

The following exampl'es will serve to illustrate the invention:

EXAMPLE 1 Preparation of 2,2-diphenyZ7iexen-4-oic acid entrainmentin theusual manner. I (Barnes, "(Organic Syntheses, 21, 78 (1941.) After the mixture was; refluxed six hours to; complete formation of theLGrignard reagent. it was filteredthrou-gh glasswool and added to a stirred solution of 11.5 g. of isocrotyl diphenyl acetate in 50 ml. of anhydrous ether. A slightly exothermic reactionwas observed. When the addi- In other instances it tion was completed the solution was warmed under reflux for thirty minutes and then was allowed to stand at room temperature forty hours. It was decomposed with slightly acidified ammonium chloride solution. The ether solution was extracted thoroughly with five per cent sodium hydroxide solution and washed with water. It was dried over sodium sulfate, filtered and distilled to yield 4.6 g. of mesitylene (B. P. Mil-162 C. (745 mm.); n 1.4961) and 0.9 g. of unchanged ester (B. P. 140-165 C. (8 mm.); M. P'. 56.557 0.). Acidification of the alkaline extracts with dilute hydrochloric acid yielded a yellow oil, which crystallized after standing fifteen minutes and was collected by filtration; M. P. of crude product 116-119 0.; yield 8. g. (74% of theory). After recrystallization from aqueous acetic acid, petroleum ether (B. P. 60 68 C.) andaqueous ethanol, the acid was obtained as white platelets; M. P. 1222-1226 C AnaZ.Calcd. for (1181 11802; 0, 31.19%; H; 6.81%; n ut. ee 266.3: Found: C,. 81.47%;; H, 6.88% neut. eq., 266;6,-268.l. V

The compound rapidly decolorized slightly alkaline permanganate solution and absorbed bromine in carbon tetrachloride solution with evolutionpthydrogen bromide, as is; characteristic of gamma, delta-unsaturated acids; Ozonization,

followed b reductive decomposition. with hydro-.

gen over a palladium catalyst- (Fischer, Diill and Ertel,v Ber. 65, 1471 (1932)), gave. acetaldehyde as the only water-soluble aldehyde isolated, which was identified; as its dimedone derivative, M- P. 140141 C.

. EXAMPLE 2 Synthesis of 21.2}diphenylherren-aoic" acz'd b'y means of phenylmagnesi'umi bromide The phenyl Grignard reagent preparedfrom 9.5 g. of bromobenzene and 1.5 g. of magnesium wasadded to 13.3 g. of isocrotyl diphenyl acetate in ether solution. The reaction mixture was allowed to stand overnight and thenwas processed inthe manner described in Example 1. The 'acid formed by the rearrangement wasisolated in a yield of 8.7 g. (66% of theory)- andwas identical with that described in Example 1.

. EX MPLE. 3

Synthesis- I means of sodium-hydride" V 7 To a stirred solution of 66 g. of isocrotyl diphenyl acetate in 60 ml. of dry benzene, 2 g. of

' tion mixture was. refluxed under a dry notrogen atmosphere, and thehydrogenevolved was col-- pulverized sodiumhydride wasadded. The reaclected in' a gas burette. Thereacjtifonwas com-f pleted in six hours, accordingt'o" the hydrogen I fication of the combined aqueous extracts evolution. After the unchanged sodium hydride was decomposed by careful: addition of methanol,

the reaction mixture was. thoroughly extracted with water and dilute sodium hydroxide. Acidi caused the precipitation of 5.6 g- (85% of theory) of a product identical with the. previously described rearrangement acid.

EXAMPLE; 2,2 -diphenyl-3-1nethyZpentene4-oic acid B a, procedure analogous to the method of Example 1 described above, 12.5.1g. ofmcrotyl diphenyl acetate dissolved in25"ml; of dry ether was caused to react with the Grignard reagent prepared from 12.0 g. of bromo-mesitylene and 1.5

of theory) M. P. 138138.5 C. after recrystallization from aqueousethanol. Ozonization followed by ca-talytic'- hydrogenation of the 'oz'onide gave formaldehyde as the only water-soluble aldehyde isolatedy M. P. of 'dimedone" dvt., l8'7188 C.; yield-52% of theory.

A'nal.--Ca1cd. fO'r (118111802: C, 81.19%; H,

Found: C, 81.34%; H,

7.10%; neut. eq 266.5. 7 EXAMPnna I 2,2-dz'phenylp'enten 4-oic acid In a manner analogous Example 1, 25g. of ally1 diphenyl acetate {in 50 rnl of, anhydrous ether was caused to react with the Grignard reagent prepared from 25 g. of

bromomesitylen'e; 3.1g. of magnesium and 75 'ml.' of ether. The yield of the acid formed by rearrangement was 11.9 g. (47% of theory); M. -P. 141.5-141.9 C.

Anal.--Calcd. for Cl'IHlSOZZ C, 80.92%; H, 6.39%; neut. eq., 252.3. Found: C, 80.73%; H, --6E5 '7%-; neut; eq., 252.9, 253.3." a

- EXAMPLE 6' iiiearraingenzen15.of beta-methylallyl diphenyl acetate (preparation ,of

2,2-diphenyl 4-methylpenten-ai-oic acid) Eleven hundred milliliters of toluene was placed in a flask and distilled until 150 ml. was removed. This was done in order to dry the equipment thoroughly. Twenty-four grams of finely divided sodium hydride was added to thetoluene under nitroge the temperautre of the mixture raised to oilingpioint. Beta-methylallyl di- 'phenyl" acetate ("1 mole) dissolved in 200 ml. of dry toluenewas added overfa periodof thirty (30) inutesfandthe whole refluxed for 22 hours after which time no more hydrogen wasievolved.

Decomposition of the reaction mixture with water gave an aqueous phase which on acidification yielded seventy-five ('75) per cent of 2,2-diphenyl-4emethylpenten-4-oic acid; M. P. 120- 122 C.

AnaZ.--Calcd. for: C, 81.17%; H, 6.81%; neut. eq., 266.3. Found: C. 80.88%, 80.99%; H, 6.92%, 6.81%; neut. eq., 2640,2646.

A EXAMPLE '1 Rearrangement: of allyl alpha-phenylbutyrate (preparation of Z-ethyZ-Z-pnenyZ penten-4-oic acid) Allyl alpha-phenylbutyrate (40.8 g.) was allowed to react with diethylaminomagnesium bromide (prepared from. 14.6 g. of diethylamine and an equivalent of ethylmagnesium bromide) in ""real "solution for 3"days 'at room temperature. Decomposition of the reaction mixture with w rand acidification of the aqueous phase gave 2:-ethyI-Z-phenyIpenten-4-oic acid; M. P. 78.5-80" C The compound readily decolorized aqueous permanganate.

Anal.--Calcd. for C13H1602I N; -E., 204.3; C, 76.44; H, 7.90. FOuIid: N. E., 204.8, 205.7; C, 76.81,

EXAMPLE 8 I Rearrangement of allyl diphenyl acetate I a In-a 2 liter three-necked flask 'equ i ppedwith a sealed stirrer, dropping funnel, nitrogen inlet tube, and arranged fordistilla'tionlwas placed one liter of pure benzenef Two hundred 'mL-of to thefrearrangin'g of poured. into the benzene while nitrogen was passed into the flask. The allyl diphenyl acetate dissolved in 100 ml. of dry benzene was added and the mixture stirred and refluxed overnight. The hydrogen evolution was slow. In the morningthere was a'heavy precipitate of the sodium salt of the product and there wasstill a slow hydrogen'evolution. The mixturewas'cooled and absolute methanol was added to decompose sodium hydride. The decomposition was slow, and was completed by adding water under nitrogen. A total of 500 ml. of water was added, and after shaking in a separatory funnel the water layer was separated and the benzene extracted with '100 ml. of 5% sodium hydroxide and then 100 ml. of water. The combined, filtered aqueous layers were treated with cooling and stirring with 90 ml. of concentrated hydrochloric acid. A gummy 'semiesolid was obtained which soon crystallized.

.slow cooling',.beautiful colorless plates were obtainedimelting at'140.5-142 C., and after drying they -weighed .4'7.4.g. This .is .2,2-diphenylp.enten-4-oic.acid.

V EXAMP E 9 Rearrangement of allyl diphenyl acetate Toluene (1300 ml.) was placed in an apparatus identical to that. described under Example 8 above, and 150 mlL of toluene was distilled. Eighteen grams (0.75 mole) of sodium hydride wasadded under nitrogen and 149 g. (0.592 mole) of allyl diphenyl acetate was added in 'ml. of dry toluene. After 20 hours'of refluxing there was no further evolution of hydrogen, so

the, reaction mixture was decomposed as described in Example '8 above.

icefbath. A solution of 100 ml. concentrated hydrochloric acid in'100 m1. of water was added rapidly until the solution became cloudy, and then it was added dropwise and the mixture seeded. The wet filter cake after washing with water weighedl29gi and was dissolved in 450 ml. of ethanol and-310 ml. of water were gradually addedto the heated solution. The solution was cooled slowly and finally chilled. After filtering, washing and drying, 83.5 g. (56%) of the 2,2-diphenylpenten-4-oicacid was obtained melting at 141"142.5 C. This product had a light yellow color which could be removed by arecrystalliz'ation in which" the solution was not chilled in the icebox, but cooled only ,under running tap,

water (30'f C.)'. I

5 V EXAMPLE 10 i freparation of allyl diphenyiacetic acid rnoles) of allyl diphenylacetate.

,8 liters of. AR. grade toluene g (5 moles) of sodium hydride I The toluene was placed in a twelve-liter; threenecked-flaskwhich Was-equipped with a dry The alkaline exv tracts were extracted once with 300 ml. of toluasaazros nitrogen inlet, an additi'onx'funnel, a lightning stirrer, and a condenser arranged for downward distillation. The flask was heated land-:80'0.:cc. of toluene were distilled to dry the apparatus completely. The receiver was changed, and .an additional 300. cc; of toluene were distilled :to be used in transferring the ester to the reaction flask. The condenser was then arranged Torrefluxing and protected from the air :by :acalcium chloride tube. The drying tube was then connected to a section of rubber tubing which led outside the building. The air in the flask was then displaced by dry nitrogen, and the stirrer was removed momentarily while three sealed parafiin tubes containing 40 'g. of sodium hydride (which had been ground in a mortar under nitrogen) apiece were added. The stirrer was'replaced, and the parafiin tubes dissolved rapidly in-the warm toluene. Heating was then continued and the toluene brought to reflux. The ester was then added rapidly, and at flrstthe solution was slightly cloudy and almost-no .hydrogen was evolved. The solution gradually developed a brown (enolate) color and the hydrogen evolution become brisk. The sodium salt of the product slowly precipitated from solution, and the mixture was left refluxing and stirring vigorously overnight, while a slow stream of dry nitrogen was passed through the system.

After sixteen hours the hydrogen evolution had stopped, but the reaction was continued for an additional four hours. At this time heating was discontinued, and when the toluene had stopped refluxing 300 ml. of dry allyl alcohol were added very slowly at first and then in a fine stream.

Heating was then resumed and the mixture refluxed for one hour to "make-certain that all the sodium hydride was decomposed. An ice bath was then substituted for the heater, and the cold mixture was stirred vigorously While 2.5 liters of water were added, slowly at first, under nitrogen. The mixture was stirred for fifteen minutes and then transferred to a separator funnel. The lower aqueous layer was brown and somewhat emulsified. toluene washed once with water. The combined aqueous extracts were then extracted once with toluene, separated and placed in a large flask equipped with a stirrer and cooled in an ice bath.

A solution of 450 cc. of cone. hydrochloric acid in 500 cc. of water was then added in a fine stream with stirring until the solution became cloudy. The mixture was scratched and seeded tocause crystallization, and the rest of the acid solution was added slowly. Toward the end of the .addition, the product formed a pasty mass, and the mixture Was left in the ice bath with-occasional swirling for one hour to insure complete crystallization. The light tan solid was filtered and washed thoroughly with cold water. After press.- ing the product with a rubber dam, the moist cake was dissolved in two liters of boiling 95% ethyl alcohol and filtered under suction to remove a small amount of finely divided solid. The hot, red-brown filtrate was treated with .600 cc. of water, at which point crystallization began. The solution was allowed to cool slowly to room temperature and then was cooled for two hours in a tap water bath at 15 C. The hard crystalline mass was crushed, and after filtering the crystals were washed with a coldsolution of 250 cc. of 95% alcohol in 250 cc. of water. After removing as much of the solvent as possible with a rubber dam, the crystals were placed in pans in a vacuum oven at 70 C. for sevenhours. The

This layer was separated and the nearlytcolorles (slight-tan color) crystals weighed 722 g. (75.2% yield) and meltedat' 140.'5 to 1-4i2 C.

EXAMPLE 11 acids having the following formula:

in which R is an aromatic radical, Rris an allphatic hydrocarbon radical, R2, R3 and R4 are selected from the group consisting of hydrogen and aliphatic radicals, and n is an integer not greater than 2 which comprises reacting an ester having the following formula:

( OI-m R: R3 R4 with an active metal hydride capableof converting said ester to an anion and rearranging said anion to introduce the allylic groupinto the alpha position to the carbonylgroup.

.-.2. Process of preparing allylic substituted acetic acids having the following formula:

in which R is an aromatic radical, R1 .is an aliphatic hydrocarbon .radicalfRz, R3 and R4 are selected from the group consisting of hydrogen and aliphatic radicals, and n is an integer not greater than 2 which comprises reacting an ester having the following formula:

| (Rm-n Ra Rs 4 with an active metal alkoxide capable of converting said ester to an anion and rearranging said anion to introduce the allylic group into the alpha position to the carbonyl group.

3. Process of preparing allylic substituted acetic acids having the following formula:

in which R is an aromatic radical, R1 is ar a-1iphatichydrocarbon radical, R2, R3 and R4 are selected from-the group consisting of hydrogen and aliphatic radicals, and n is an integer not in which R. is

greater than 2 which comprises reacting an ester having the following formula:

with a Grignard reagent capable of converting said ester to an anion and rearranging said anion to introduce the allylic group into the alpha position to the carbonyl group.

5. Process of preparing allylic substituted ace tic acids having the following formula:

which comprises reacting an ester having the following formula:

CaHs O CH-C CH-C=CH 05115 H H H with an active metal hydride capable of converting said ester to an anion and rearranging said anion to introduce the allylic group into the alpha position to the carbonyl group.

6. Process of preparing allylic substituted acetic acids having the following formula:

in which R is an aromatic radical, R1 is an aliphatic hydrocarbon radical, R2, R3 and R4 are selected from the group consisting of hydrogen and aliphatic radicals, and n is an integer not greater than 2, which comprises reacting an ester having the following formula:

with a. basicreagent cap-able of converting said ester to an anion, said basic reagent being selected from the group consisting of active metal hydrides, active metal alkoXides, active metal amides, and Grignard reagents, and rearranging said anion to introduce the allylic group into the alpha position to the carbonyl group.

'7. Process of preparing allylic substituted acetic acids having the following formula:

which comprises reacting an ester having the following formula:

with an active metal amide capable of converting said ester to an anion and rearranging said anion to introduce the allylic group into the alpha position to the carbonyl group.

RICHARD T. ARNOLD.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Name Date Groll et a1 June 2'7, 1939 Number OTHER REFERENCES Kimel et al.: Chem. Abstracts, vol. 38, col. 66

Adams et 21.: Organic Reactions" (Wiley) VOL pp. 2-6 (1944),

Certificate of Correction October 17 1950 Patent N 0. 2,526,108

' RICHARD T. ARNOLD certified that error appears in the printed specific patent requiring correction as follows:

tion of the formula readin --C--CH for notrogen ation of the It is hereby above numbered Column 1, line 40, for that por read -0'-=OH; column 4, line 16, for 8. g. read 8.5 g.; line 55,

column 5, line 36, for temperautre read temperature;

ed above, so that the read nitrogen; and that the said Letters Patent should be read as correct form to the record of the case in the Patent Oflice.

same may con Signed and sealed this 2nd day of January,

' THOMAS F. MURPHY,

Assistant Oommtgsioner of Patents. 

1. PROCESS OF PREPARING ALLYLIC SUBSTITUTED ACETIC ACIDS HAVING THE FOLLOWING FORMULA: 